Applicants claim the benefit of priority from International Application PCT/EP99/00185.
1. Field of the Invention
The present invention relates to a microdosing device.
2. Description of Prior Art
Precise dosing of extremely small volumes of fluid in the range between 0.01 xcexcl and 1 xcexcl is of great and decisive importance e.g. in the fields of biotechnology, DNA analytical chemistry and combinatorial chemistry. According to the prior art, dispensers or pipettes are predominantly used for dosing small volumes. In these cases, the volume to be dosed is displaced either directly, by a so-called piston-type direct displacement, or via an intermediate air cushion. In this respect, reference is made e.g. to the article xe2x80x9cPipettieren und Dispensierenxe2x80x9d, A. Jahns, Fachzeit-schrift der Technischen Assistenten in der Medizin, volume 8 (1993), No. 12, pages 116-1172, Umschau Zeitschriftenver-lag.
Air-cushion pipettes are suitable for dosing volumes between 0.01 xcexcl and 5 ml, accuracies of xc2x12-3% being achieved in the case of volumes exceeding 1 xcexcl. In the case of smaller volumes, however, the accuracies achieved are only accuracies of approx. xc2x110% due to surface effects at the tip of the pipette. The limited dosing accuracy in the case of smaller volumes is predominantly due to the fact that the tip of the pipette or dispenser must be immersed into the medium to be dosed, whereby the dosing amount will be influenced by effects such as surface tension, wetting and hydrostatic pressure. In order to avoid these problems as well as the risk of carrying over media due to immersion, a dosing system should be based on the discharge of the dosed volume in a free jet. Direct-diplacement dispensing devices offer this additional advantage, but only in the case of volumes of approx. 10 xcexcl and more.
Known systems discharging extremely small volumes of fluid in a free jet are ink-jet printheads. Ink-jet printheads are known which are based on two fundamentally different principles, viz. those which are effective making use of thermal transducers and those which are effective making use of piezoelectric transducers. In this respect, reference is made to the publications N. Schwesinger: xe2x80x9cPlanarer Tinten-strahldruckkopfxe2x80x9d. FandM, 11-12; pages 456-460; 1993; H. Bentin, M. Doering, W. Radtke, U. Rothgordt: xe2x80x9cPhysical Properties of Micro-Planar Ink-Drop Generatorsxe2x80x9d. J. Imaging Technology, 3; pages 152-155; 1986; and Wolfgang Wehl; Tinten-drucktechnologie; Paradigma und Motor der Mikrosystemtechnik; Feinwerktechnik and MeBtechnik; part 1 in edition 6/95, part 2 in edition 9/95.
In the case of printheads operating according to the xe2x80x9cdrop-on-demandxe2x80x9d principle, a small ink drop is flung in a free jet onto a paper after the application of a voltage pulse. A typical drop diameter is approx. 60 xcexcm, i.e. the volume is approx. 0.0001 xcexcl. Normally, these printheads are, however, only adapted to be used in combination with special inks. Media which are used e.g. in the field of biotechnology are in most cases very different from these inks as far as viscosity and surface tension are concerned. However, the viscosity and the surface tension substantially influence the size of the drops and, consequently, the volume dosed. Furthermore, a generation of drops is only possible in a very limited viscosity range. The volume of the individual drops can, moreover, only be modified in a very limited range by modifying the control pulses.
Furthermore, dosing systems are known, which are also capable of generating drops in the case of media having strongly different viscosities. Such a system is described e.g. in the publication xe2x80x9cMikrodosierungxe2x80x9d, company publication of the firm of microdrop GmbH, Norderstedt, 1995. As in the case of ink-jet printheads, the drop volume is here determined predominantly by the size of the nozzle diameter. only to a very limited extent can it also be influenced by the electric control of the actuator. As in the case of ink-jet printheads, the process of drop tearing at the nozzle depends, however, on the physical properties of the media to be dosed, i.e. on the viscosity, the surface tension, etc. The exact size of the drops is therefore again strongly media-dependent. The dosing of a desired volume, which lies in the range between 0.1 xcexcp and 1 xcexcl in most cases, is based the counting of individual drops of the same size. The typical volume of an individual drop is smaller than 0.001 xcexcl. Since the volume errors of the individual drops will, however, accumulate in this process, the dosing accuracy is strongly limited.
An increase of this dosing accuracy is only possible with the aid of complicated and expensive systems. An image processing system can, for example, be used by means of which the size of the individual drops can be determined and the number of drops required can be calculated during a dosing process. Furthermore, according to an alternative method of increasing the dosing accuracy, a fluorescent substance can be admixed to the medium to be dosed. In the case of this alternative method, the dosing process will be finished when the intensity of the fluorescent signal reaches the set value. It is, however, easily evident that the above-mentioned methods of increasing the dosing accuracy are both very complicated and expensive.
EP-A-0439327 discloses a control system for a micropump, which is adapted to be used e.g. in a dosing device. The control system selectively controls the generation of drive pulses so as to control the discharge of fluid through the pump. This known control for a micropump uses respective square-wave signals having different amplitudes so as to control a piezoelectric driver element which serves to drive a pump membrane.
EP-A-0725267 discloses an electrically controllable micropipette for handling extremely small fluid volumes in the range of a few hundred pl to a few xcexcl. The main component of this known micropipette is a micromembrane pump operated as a microejection pump; a second micromembrane pump can additionally be provided, which is implemented as a micropressure or a microsuction pump. Each of these respective pumps is controlled by square-wave voltages.
In the prior, non-prepublished German application 19706513.9-52 owned by the applicant of the present application and filed on Feb. 19, 1997, a microdosing device is disclosed, which permits a discharge of exactly defined volumes of fluid. This application discloses a microdosing device comprising a pressure chamber which is at least partly delimited by a displacer. An actuating device for actuating the displacer is provided, the volume of the pressure chamber being adapted to be changed by actuating the displacer. A media reservoir is in fluid comunication with the pressure chamber via a first fluid line, whereas an outlet opening is in fluid communication with the pressure chamber via a second fluid line. For causing a defined fluid volume to be discharged from the outlet opening, the above-mentioned publication discloses that there are provided a means for detecting the respective position of the displacer and a control means which is connected to the actuating device and to the means for detecting the position of the displacer, the control means controlling the actuating device on the basis of the detected position of the displacer or on the basis of displacer positions detected during at least one preceding dosing cycle.
By means of the microdosing device disclosed in the above-mentioned German application 19706513.9-52 it is possible to eject exactly defined volumes of fluid independently of the vicosity of the fluid to be dosed by controlling the actuator of the displacer on the basis of the output signals of the volume sensor. It follows that the defined fluid volume is almost independent of the viscosity, surface tensions, etc. of the medium to be dosed. It follows that media which differ with regard to viscosity and surface tensions can be dosed according to the above-mentioned German application, such media being used e.g. in the field of biotechnology.
It is the object of the present invention to provide an uncomplicated microdosing device permitting, within an operating range, a dosing operation which is independent of the viscosity of a medium to be dosed.
This object is achieved by a volume sensor-free microdosing device comprising a pressure chamber which is at least partly delimited by a displacer, an actuating device for actuating the displacer, the volume of the pressure chamber being adapted to be changed by actuating the displacer, a media reservoir which is in fluid communication with the pressure chamber, an outlet opening which is in fluid communication with the pressure chamber, and a control means. With the aid of the control means the microdosing device is driven in such a way that a small change of volume is effected per unit time by a movement of the displacer from a first position to a predetermined second position, the second position of the displacer defining a larger volume of the pressure chamber than the first position, so as to suck a fluid volume into the pressure chamber. During a second phase, the control means drives the microdosing device in such a way that, by means of a movement of the displacer from the second position to the first position, a large volume change of the pressure chamber volume is effected per unit time so as to eject a defined fluid volume from the outlet opening in this way.
The present invention is based on the finding that it is possible to provide a viscosity-independent dosage in a sufficiently large, interesting operating range even if the volume sensor means, i.e. a means for detecting the position of the displacer, is dispensed with in the microdosing device disclosed in the above-mentioned German application 19706513.9-52. This viscosity independence of the dosing process, which suffices for many cases of use and which is described in the present application, is not disclosed in the above-mentioned German application 19706513.9-52, since the ejection of a defined fluid volume, essentially viscosity independent, is there precisely carried out on the basis of such a volume sensor means.
According to the present invention, fluid is ejected due to a direct displacement of the fluid, in contrast to acoustic principles which are used in most ink printheads. In such ink printheads, especially in printheads which are driven piezoectrically, a pressure wave is normally produced in the dosing chamber which propagates in the direction of the nozzle and which causes the drop to tear at the nozzle. The drop diameter will here essentially correspond to twice the cross-section of the nozzle. In contrast to this, a pressure wave is generated by a vapour bubble in known, so-called bubble jet printers; the displacement caused by the vapour bubble is limited to a volume of approx. 50 to 100 pl due to the size of the vapour bubble and cannot be substantially increased due to physical principles. This will typically have the effect that an individual drop having a size of the order of twice the cross-section of the nozzle will tear, whereas according to the present invention a jet of fluid is obtained whose total volume is much larger than this individual drop.
In each mechanism used for generating individual drops, the exact tearing of the drop and, consequently, the dosed fluid volume depends on many details, such as e.g. the viscosity, the surface tension of the fluid, the temperature, the control voltage, etc. In these individual-drop mechanisms both the drop size and the formation of a xe2x80x9cdrop tailxe2x80x9d, which is produced when the drop tears, differ. It follows that a different viscosity leads to a variation of the dosed volume of an individual drop, the absolute dosing errors of each individual drop being summed up by the summation of the individual drops when the whole volume to be dosed is being produced. Hence, the relative dosing error of the total volume corresponds to the relative dosing error of each individual drop.
It is now the concept of the present invention to eject a substantially larger amount of fluid than an individual drop with high kinetic energy. The ejected amount of fluid may have the volume of approx. 10 to 1,000 individual drops, these values being, however, only indicated by way of example. According to the present invention, the effects occurring when the fluid jet tears will therefore only influence the beginning and the end of the fluid jet, and, with respect to the total dosing volume, these effects will only be of secondary importance. The predominant portion of the fluid amount discharged from the outlet opening or the nozzle is determined by inertia and friction.
It follows that in the case of the method according to the present invention, which is based on a direct displacement of the fluid, the error caused by the tearing of a drop will occur only once for the whole amount of fluid. Whereas the summation of 10 to 1,000 individual drops in individual-drop meachanisms entails a summation of the erros the individual drops, the present invention permits, roughly speaking, the error to be reduced by the number of individual drops contained in the dosed fluid amount. In this connection, reference should be made to the fact that also according to the present invention the fluid jet can disintegrate into individual drops when it has left the nozzle. This will, however, no longer have any influence on the total dosing amount, since the fluid has already left the nozzle. Moreover, an even more precise dosage can be achieved when the actuating device and the displacer are implemented with a stiffness of such a nature that the displacer is essentially forcibly controlled.
The media reservoir can be connected to the pressure chamber via a first fluid line, whereas the outlet opening can be connected to the pressure chamber via a second fluid line.
According to a preferred embodiment of the present invention, the control means controls the actuating device in such a way that the volume changes described are caused. For this purpose, the control means can control the actuating device in the first phase with a first signal of low edge steepness, whereas this control means controls the actuating device in the second phase with a second signal of high edge steepness. A fluid movement in the first and second fluid lines is therefore substantially inertia independent in the first phase, whereas a fluid movement in the second phase is essentially determined by the relation of the fluid inertias in the first and second fluid lines.
Alternatively, the displacer, when implemented as a membrane, can be adapted to be pretensioned by the actuating device such that it occupies a first position, the membrane being not fixedly connected to the actuating device so that, in response to an actuation of the actuating device at the beginning of the first phase, the movement of the membrane from the first position to the second position will take place only due to the restoring force of the membrane. This is another possibility of causing a small volume change of the pressure chamber volume per unit time when the displacer moves from the first position to the second position. The restoring force of the membrane is preferably dimensioned such that the negative pressure caused by the restoring force in the pressure chamber is smaller than a capillary pressure prevailing in the second fluid line.
The present invention additionally provides a method of calibrating a microdosing device of the above-mentioned type so that, after a single calibration, reproducible results are obtained during subsequent dosing phases. The microdosing device according to the present invention can also be used as a pipette by immersing, during the above-mentioned first phase, the outlet opening into a fluid to be pipetted.
When the microdosing device is put into operation for the first time, the pressure chamber and the fluid lines are first filled with a fluid prior to activating the actuating device in the first phase for sucking in a fluid. The microdosing device according to the present invention can be produced in an advantageous manner making use of micromechanical methods, especially methods in the field of semiconductor technology. Furthermore, the microdosing device according to the present invention can have a modular structural design of such a nature that e.g. the pressure chamber, the displacer and, optionally, at least parts of the first and of the second fluid line are implemented as a replaceable module by means of micromechanical methods. Furthermore, the media reservoir can be a part of the replaceable module; in this case, it is also produced by means of micromechanical methods.
As has already been explained, an essential advantage of a dosing process according to the present invention is to be seen in the fact that a fluid jet as a whole is discharged and that there is no need of adding a plurality of individual drops for obtaining the desired dosing volumes e.g. in the field of biotechnology. Although the exact tearing of the free jet at the outlet opening is influenced by the properties of the media, as in the case of conventional systems, a higher dosing accuracy is still obtained according to the present invention. Since the media displacer of the microdosing device according to the present invention is easily able to discharge also larger volumes in the desired range between 0.01 xcexcl and 0.1 xcexcl in the course of a process, volume errors, which are a result of the tearing of the individual drops and which would represent a comparatively large relative error in the case of drop volumes of 0.0001 xcexcl, are no longer of any importance. A summation of the systematic errors per drop no longer occurs according to the present invention.
When the displacer is being returned to the second position, whereby the volume of the pressure chamber is reduced, so as to eject the fluid through the outlet opening in the form of a free jet, the movement of the fluid in the first fluid line, i.e. the reservoir channel, and in the second fluid line, i.e. the nozzle channel, is determined almost exclusively by the relation between the fluid inertias in the respective fluid lines, the relation between the flow resistances of the fluid lines being, however, negligible. The defined fluid volume, which is ejected by means of the microdosing device according to the present invention, is therefore almost independent of the viscosity, surface tensions, etc. of the medium to be dosed. The present invention can therefore be used for dosing media having different viscosities and surface tensions, this kind of media being used e.g. in the field of biotechnology.
The microdosing device according to the present invention can also be used for pipetting a fluid and a liquid, respectively. For this purpose, a fluid is sucked in via the outlet opening, which can also be referred to as nozzle, e.g. by immersing the nozzle into a fluid to be pipetted. Subsequently, the sucked-in fluid is discharged in a free jet, as has already been described. Sucking in can be effected e.g. by a negative pressure in the media reservoir, which causes a suction effect, or by a suitable movement of the actuator. The microdosing device according to the present invention is also suitable to be used as a pipette in the case of which the outlet opening of the pressure chamber filled with an inert fluid is immersed into a fluid to be pipetted during the first phase, or a previously unfilled system is filled due to a capillary action alone, when the system is being immersed into the fluid.
Further developments of the present invention are disclosed in the dependent claims.